FormalPara Key Summary Points

This review aims to identify key biomarkers linked to immune activity, genetic predispositions, neuron integrity, metabolism, and pain pathways to improve the diagnosis, treatment, and prediction of postherpetic neuralgia (PHN), thereby enhancing patient quality of life.

Challenges such as high analysis cost, limited sample sizes, and lack of universal cohorts may constrain biomarker integration into clinics.

Future studies with large cohorts will be required to find move effective biomarkers and develop precise predictive models for personalized PHN treatment.

Introduction

Herpes zoster (HZ), commonly referred to as shingles, is an illness triggered by the reactivation of the varicella-zoster virus (VZV). It predominantly manifests as pain and rashes that follow the nerve pathways. Pain, often described as burning, cutting, stabbing, or resembling electric shocks, is usually accompanied by severely intense hypersensitivity. The incidence rate of HZ is approximately 0.523–1.09% annually. While most patients experience pain alleviation and convalescence within weeks, between 5 and 30% of patients may progress to postherpetic neuralgia (PHN) [1]. Currently, first-line treatments for PHN in clinical practice include antiepileptic drugs and tricyclic antidepressants, but their efficacy is often suboptimal, or their side effects are intolerable [2]. The course of PHN can extend over several years or decades, with persistent intense pain causing immense distress to patients. This significantly impairs quality of life and productivity, possibly resulting in insomnia, anxiety, depression, and potentially suicide [3].

The cornerstone of PHN prevention hinges on the identification of high-risk individuals via effective strategies, enabling early and standardized interventions [4]. At present, the primary determinants of PHN risk are discerned via clinical indications, despite their broad diversity and lack of specificity. This underscores the pressing clinical need for more reliable, objective, and measurable biomarkers to facilitate accurate prevention. The purpose of this review is to detail the latest research progress on PHN biomarkers evaluated through hematological and pathological tests and auxiliary examinations [5, 6]. This approach might enable early PHN detection, thereby averting catastrophic outcomes.

Postherpetic Neuralgia

Following initial infection with VZV, children typically develop chickenpox. Even after recovery, the virus may remain dormant in various areas, such as the spinal dorsal root ganglia. Reactivation of this dormant VZV can occur when immune responses are compromised due to various factors, leading to expansive viral replication. This can result in the virus traveling along nerve fibers to the skin, causing rashes. Concurrently, the activation of local immune-inflammatory responses may cause rashes, destruction of nerve fiber endings, and increased nerve fiber sensitivity, resulting in hyperalgesia and touch-induced pain [7].

Clinical Risk Factors for Postherpetic Neuralgia

Currently, the clinical prediction of PHN is largely based on a variety of patient attributes and factors associated with shingles. These include age, sex, prodromal symptoms, and the severity of acute pain during the initial infection stages [8]. Additionally, factors such as touch-induced pain, numbness, interference with daily life, the severity and extent of the rash, the presence of rashes in specific areas (e.g., eyes, perineum), and severe immunosuppression (e.g., human immunodeficiency virus [HIV] infection, new tumors, high-dose hormone therapy, hematopoietic stem cell transplantation, hematologic malignancies, systemic lupus erythematosus, inflammatory bowel disease) have been identified as potential indicators of PHN development [9, 10]. Furthermore, certain conditions, including surgery, trauma at the site of infection, tumor growth, tuberculosis, hepatitis B infection, hypertension, diabetes, coronary heart disease, angina, smoking, and alcohol addiction, have been identified as risk factors for PHN [11, 12].

Numerous pain centers have used extensive datasets to construct predictive models for the incidence of PHN [13,14,15,16]. In our research, we specifically developed a predictive model to evaluate the success of pulsed radio-frequency therapy in mitigating herpes zoster neuralgia [17]. Notably, our model identified various risk factors for PHN development, including male sex, extended duration of herpes zoster infection, higher doses of pregabalin, a higher 36-Item Short Form Health Survey (SF-36) somatic pain index score, a lower peripheral blood lymphocyte count, and decreased levels of low-density lipoprotein and complement C4. Upon the analysis of these findings, we successfully formulated a predictive model.

The discrepant methodologies of different clinical observation items, coupled with sample size variations and regional differences, have given rise to inconsistent results and differing weights for high-risk factors. Consequently, the research findings have yet to reach a uniform consensus. For instance, some research studies have shown that females younger than 60 years have a greater risk of PHN and females older than 60 years have a lower risk of PHN than males of the same age [18]. Consequently, these clinical high-risk factors exhibit low sensitivity and a notable measure of uncertainty, which hampers their clinical value. Therefore, the identification of more sensitive biomarkers is imperative.

Biomarkers for Postherpetic Neuralgia

The consistent escalation in the use of reliable biomarkers, including blood tests, pathological evaluations, and additional diagnostic methods, is currently leveraged to identify high-risk populations [5, 6]. These advancements have significantly enhanced the ability to predict PHN. The biomarkers identified in this discussion (Fig. 1) span a broad spectrum, covering immune cell variations, cytokines, blood proteins, genetic and DNA expression analyses, proteomics and metabolomics studies, epidermal nerve fiber counts, functional magnetic resonance imaging (fMRI) and electromyography evaluations, and infrared thermographic techniques, among others.

Fig. 1
figure 1

Potential biomarkers for postherpetic neuralgia

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Immunological Biomarkers

Immune Cells

Upon reactivation of VZV, dendritic cells (DCs) detect the virus, leading to upregulation of major histocompatibility complex (MHC) class I and II proteins. This event triggers the release of substantial inflammatory factors. Consequently, natural killer (NK) cells, along with VZV-specific T cells, are activated, facilitating the infiltration of CD4+ and CD8+ T cells, which causes ganglion necrosis. Decreased immunity mediated by VZV-specific T cells is associated with the onset of HZ. Postherpetic ganglioneuritis and persistent infiltration of CD8+ T cells can amplify the response to benign stimuli over an extended period (Fig. 2) [19, 20]. Extensive studies have investigated the role of immune cells as biological markers for PHN, and several key findings are presented here.

Fig. 2
figure 2

Pathogenesis of postherpetic neuralgia. The mechanism of action of immune cells in postherpetic neuralgia (A). The self-destruction of skin cells and fibroblasts driven by viruses leads to the appearance of rashes. Concurrently, immune-inflammatory actions stimulate peripheral nerve endings and amplify their sensitivity, thereby inducing intense pain and heightened sensitivity to touch. Post-VZV reactivation, MHC class I and II protein levels increase, and both CD4+ and CD8+ T cells invade the ganglia, causing tissue death and bleeding. The onset of HZ has been linked to a decrease in the VZV-specific defense provided by T cells. The pathogenesis of postherpetic neuralgia (B). After damage to peripheral nerves occurs, the expression of voltage-gated sodium channels and the function and expression of transient receptor potential channels are altered in the injured sensory nerve fibers. These changes lead to increased spontaneous activity, rendering the nerves hyperexcitable and resulting in allodynia and hyperalgesia, common symptoms of PHN. On the central side, a sustained barrage of atypical nerve impulses from the periphery drives central sensitization. This results in enhanced responsiveness to both painful and non-painful stimuli. ACC anterior cingulate cortex, DRG dorsal root ganglion, HZ herpes zoster, MHC major histocompatibility complex, NK natural killer, PFC prefrontal cortex, PHN postherpetic neuralgia, S1 primary somatosensory cortex, VZV varicella-zoster virus

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Neutrophil-to-Lymphocyte Ratio

The diminished functionality of the immune system, attributable to immune cells, serves as a definitive risk factor for the occurrence of HZ and PHN. The neutrophil-to-lymphocyte ratio (NLR) is commonly used to assess lymphocyte function in clinical settings. Studies of patients with rheumatic conditions have shown an increase in the NLR among those infected with HZ [21]. Furthermore, research conducted on patients who underwent liver transplants suggested a close correlation between a patient’s preoperative NLR and susceptibility to HZ and PHN [22]. Investigations into Ramsay Hunt syndrome illustrated that patients with a relatively high NLR presented significantly elevated grades of House–Brackmann (HB) facial paralysis, subsequently diminishing the likelihood of complete recovery [23]. The efficacy of minimally invasive treatment for PHN is pervasively influenced by a decrease in lymphocyte count; changes in the number and proportion of lymphocytes directly impact both the occurrence of PHN and the effectiveness of interventions [17]. An increased NLR is associated with an increase in neutrophils and a decrease in lymphocytes; a reduced lymphocyte count generally signifies impaired cell-mediated immune function, while an increase in neutrophils translates to an enhanced systemic inflammatory response. The activation of neutrophils may suppress T-cell proliferation and cytotoxic behaviors by binding PD-L1 in neutrophils to PD-1 in T cells, resulting in immune suppression [24]. Aberrations in the NLR can offer insightful and critical data for predicting the progression and prognosis of both HZ and PHN.

T Cells and Subtypes

Notably, patients suffering from HZ neuralgia exhibit diminished cell-mediated immune function, evidenced principally by T-lymphocyte dysfunction. An increase in HZ infections among patients with COVID-19 has prompted researchers to suspect a potential connection to T cell dysfunction—characterized by a decrease in cell volume and functional exhaustion—induced by the novel coronavirus [25]. Studies of T-lymphocyte subclasses in patients with HZ revealed a decrease in the numbers of CD3+ T cells and CD8+ T cells with aging and during the development of PHN [26]. Intriguingly, prior to the traditional manifestation of HZ, a decreasing ratio of T-cell subgroups (CD4+ T/CD8+ T cells) was observed. However, this ratio increases after the emergence of rashes and returns to normal once the lesions disappear. This pattern suggests that an immune imbalance is a potential catalyst for viral activation [27]. A study comprising 76 patients with HZ discerned an inverse relationship between CD4+ T lymphocytes and the severity of pain: the more severe the pain, the more significant the reduction in lymphocytes [28]. This finding indicates an impairment of T-cell immunity predominantly in severe cases of HZ. Moreover, the study revealed a substantial increase in the proportion of regulatory T cells (Tregs) in patients with HZ, which could suppress the immune response to antiviral CD4+ T cells due to increased Treg cell activation. Scrutinizing the number of T cells and their immune functions could serve as indicators of the risk of PHN development. A decrease in the number of T cells and inhibition of their function could cause an HZ outbreak, potentially leading to chronic disease and, notably, PHN sequelae.

VZV-specific cell-mediated immunity (VZV-CMI) is recognized for its vital role in activating T cells that combat VZV, which results in efficient virus elimination. HZ originates from a decrease in VZV-specific T-cell immunity, often consequent to aging or immune suppression. This causes reactivation of the latent VZV within the sensory ganglia [29]. In the skin, VZV-specific T cells selectively infiltrate and remain at the rash site compared to the opposing site [30]. Further support for this viewpoint comes from the detection of VZV DNA and proteins in the peripheral blood mononuclear cells (PBMCs) of patients suffering from PHN. Taken together, these findings suggest that low-level viral ganglionitis contributes to PHN and heightens the chance of prolonged viral infection, possibly extending months beyond the clinical remission of HZ [31]. In contrast, patients with diminished VZV-CMI often exhibit persistent VZV DNA detection in saliva and are more susceptible to PHN [32]. These patients struggle to control viral replication and may undergo persistent viral shedding, facilitating the onset of PHN. In elderly individuals, increased age or depletion of VZV-specific T cells in PBMCs results in a degraded effector T-cell response to HZ [33]. Treg cells accumulate at the infection sites in elderly individuals and could further suppress the activity of other functionally normal VZV-specific T cells, thereby encouraging PHN development [34]. These findings support current strategies for formulating new shingle vaccines designed to stimulate cell-mediated immunity, prevent VZV reactivation, and avoid the development of shingles and PHN. An initial poor response of VZV-specific T cells or persistent VZV presence in saliva could serve as diagnostic markers, thereby paving the way for more precise treatment plans for high-risk patients with PHN.

Comprehensive Immune Cell Atlas

As detection technology and accuracy continually evolve, the classification of immune cell types becomes increasingly granular, inevitably enhancing the sensitivity and specificity of PHN predictions. Our research group systematically employed cytometry by time-of-flight (CyTOF) technology in previous studies to examine the temporal changes in all immune cell subgroups in the peripheral blood of patients with HZ-related neuropathic pain. We characterized and analyzed the dynamic changes in six primary immune cell clusters, namely, CD4+ T cells, CD8+ T cells, γδ T cells, NK cells, B cells, and myeloid cells [6]. Our findings indicated diverse rhythmic alterations over time, revealing patterns of rapid and slow responses. Primarily, the changes in T cells were most notable, as evidenced by the decreasing ratio of CD4+/CD8+ T cells. Further investigation of 40 immune cell subclusters revealed that the T02, T03, T10, T18, and T25 clusters were significantly greater in patients with PHN than in those experiencing pain relief. Concurrently, the levels of tumor necrosis factor alpha (TNF-α) produced by cells in the T02 and T18 clusters and other immune cell subgroups, as well as VZV-specific T cells, were greater than those in patients who did not progress to PHN. All T-cell subgroups with slow response patterns were negatively correlated with clinical pain-related scores. The T02 and T18 clusters in patients who experienced pain relief (the non-PHN group) were significantly greater than those of patients with PHN. Moreover, we found that in patients with PHN, the levels of PD-1+ CD4+ T cells, VZV-specific PD-1+ CD4+ T cells, and TNF-α produced by VZV-specific T cells were greater than those in patients without PHN. However, confirming the predictive ability of these markers requires extensive large-scale data validation.

Other Immune Cells

NK cells, intrinsic cytotoxic lymphocytes, play a pivotal role in antiviral immunity and are particularly evident in VZV infections. Individuals with NK cell deficiencies often exhibit heightened vulnerability to intense, sometimes lethal, VZV infections [20]. A decrease in both NK cell and VZV-specific T-cell populations indicates an increased risk for VZV resurgence, culminating in shingles [19]. Frequent HZ infections are reported among kidney transplant recipients receiving prolonged immunosuppressive therapy, and the long-term HZ prevalence in these patients correlates directly with NK cell counts measured 6 months post-transplant [35].

DCs, specialized antigen-presenting cells, act as pivotal immune actors during viral incursions, orchestrating the onset and regulation of antiviral immune responses. Recorded evidence indicates successful VZV infection of both immature and mature monocyte-derived DCs, Langerhans cells (LCs), and plasmacytoid dendritic cells (pDCs) [36]. Monocytes and macrophages are paramount for recognizing pathogens, bolstering immune defense, and orchestrating inflammation resolution. Monocyte invasion and microglial proliferation often coincide with demyelination [37]. Acute ganglia infections exhibit nuclear inclusions, viral antigens, and VZV entities. Moreover, the connection between VZV viremia and both primary VZV infection and reactivation was confirmed by identifying interactions between monocytes and VZV during these phases.

Cytokines

The interplay between proinflammatory and anti-inflammatory cytokines critically shapes the mechanisms involved in neuropathic pain [38]. Proinflammatory cytokines, including TNF-α, interferon gamma (IFN-γ), interleukin (IL)-1β, and IL-17, can directly or indirectly intensify neuronal excitability and attenuate pain thresholds by stimulating signaling pathways within neurons, glial cells, and immune cells, subsequently leading to pain genesis. In contrast, anti-inflammatory cytokines such as IL-10 and IL-4 alleviate pain through the activation of specific pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, while concurrently impeding the release of proinflammatory cytokines. Current research on immune–neuromolecular interactions emphasizes the imbalance of inflammatory factors in patients with neuropathic pain.

IFN, a key antiviral defense and regulatory factor within the immune system, has significant implications for patients with primary immunodeficiencies characterized by defects in IFN signaling pathways, which increase susceptibility to acute VZV infection. Rare downstream genetic defects in the type I IFN signaling pathway heighten susceptibility to varicella and other viral infections [39]. VZV-encoded genes can limit type I IFN production, thus regulating the signal transduction of type I IFN [40, 41]. This diminished function is partly due to the inhibition of intrinsic function and the presence of autoantibodies. Of five PHN test subjects who tested positive for antibodies against cellular cytokines, three had antibodies against IFN-α [42]. In vitro studies revealed that IFNs significantly curtail VZV transcription and virus propagation by inhibiting the replication ability of VZV in cultured human neurons [43]. Notably, dorsal root ganglion injections of IFN-α2b can alleviate pain and reduce the incidence of PHN, as evidenced by long-term follow-up [44]. Further research into IFN subtypes revealed that patients with PHN exhibited distinctly greater expression of IFN-A1/13 and IFN-A2 than the control group and greater expression of IFN-4 and IFN-10 than the HZ group [45]. The use of specific IFN tests could identify a cohort of high-risk patients with PHN with increased IFN expression, allowing for targeted therapy to alleviate IFN expression and prevent the onset of PHN.

In the acute phase, serum levels of the IL-6 protein were elevated in patients who subsequently developed PHN, and this elevation was positively correlated with pain severity [46]. Furthermore, patients suffering from severe VZV infection exhibited a significant increase in serum IL-6 levels, which were positively correlated with the effectiveness of treatment for shingles-related pain [47]. These observations suggest that serum IL-6 levels during the acute phase of shingles could serve as a reflection of disease severity and are closely related to pain intensity and prognosis, thus playing a key role in the onset of PHN. It was also found that serum IL-10 levels increased significantly in patients with severe VZV infection, suggesting that it is a potential predictive factor for PHN duration. The origin of IL-10 in the serum has not been determined; however, Treg cells are a potential source of IL-10 [48]. Furthermore, a comparative study revealed a considerable increase in the proportion of Treg cells within the CD4+ T cells in patients with acute HZ in comparison to healthy controls [28]. An early increase in serum IL-10 levels could be an essential biological marker for PHN manifestation. Elevated levels of IL-18 were also observed in patients with HZ and were correlated with the intensity of rash and pain [49]. Genome-wide association studies (GWAS) of two different IL-18 proteins revealed a correlation between the predicted increase in IL-18 protein levels and increased susceptibility to PHN. Consequently, these findings suggest that increased IL-18 protein levels may amplify the risk of PHN, which could contribute to the development of new prevention and treatment strategies for PHN [50].

Differences across these studies may result from individual differences or variations in disease onset stage. Notably, PHN onset typically involves a collection of cytokines, and the lack of a reliable multi-cytokine predictive model underscores the need for additional research and the use of big data to develop accurate prediction models. Current cytokine detection methods have limitations, especially in detecting and analyzing rare cytokines. However, with rigorous research, the development of multi-cytokine predictive models and personalized prediction models accounting for individual clinical presentations, and increased analysis of specific cytokine subtypes, cytokines have the potential to revolutionize PHN prediction.

Nerve Injury-Related Proteins

Certain proteins associated with neurotrauma may function as novel predictors of related neurological disorders. Accordingly, numerous research efforts have been directed toward exploring the prospective predictive value of these specific circulatory biomarkers of neuronal injuries for PHN. A key protein being studied is neuron-specific enolase (NSE). Given that nerve damage results in its prolific release, NSE concentration has emerged as a barometer for the severity and future trajectory of neurological ailments [51]. Clinical studies have also shown a relationship between NSE concentrations and the severity of PHN [52]. As NSE levels taper off, both the condition and pain-related symptoms markedly improve. This finding mirrors the strong association between NSE concentrations and short-term outcomes in patients with PHN, with both high sensitivity and specificity as an indicator for PHN. Myelin basic protein (MBP), which is fundamental to myelin sheaths, not only boosts signal propagation but also operates as a potential autoantigen. It can stimulate T cells, playing a vital role in diseases characterized by myelin sheath deterioration [53]. Investigations into the relationship between circulating MBP concentrations and PHN have revealed that patients diagnosed with PHN often exhibit increased MBP levels during the early stages of HZ relative to those who do not develop PHN [54]. These findings suggest that MBP might be involved in the pathogenesis of PHN and could function as a prognostic marker. An increase in plasma galectin-3 concentrations has been noted in patients with breast cancer receiving paclitaxel for chemotherapy-induced peripheral neuropathy (CIPN), as well as in murine models of paclitaxel-triggered CIPN. A retrospective examination revealed a notable increase in the serum galectin-3 concentration in patients with HZ-associated early neuralgia (HZ-EN) and patients with PHN, revealing a positive relationship with pain intensity. These findings suggest that galectin-3 could play a part in the onset and progression of HZ-EN and PHN [55]. For instance, the presence of the blood‒brain barrier complicates the identification of nerve injury-associated proteins that seep into the bloodstream in minuscule amounts. Moreover, serum biomarkers generally exhibit a temporal lag following nerve injury. Challenges notwithstanding, serum analysis remains a feasible, readily accessible, and ultrasensitive modality for assessing the severity and progression of nerve trauma, thereby offering predictive insights into the likelihood of developing PHN.

Genetics

There is significant research focusing on the genotype of genes related to PHN, with human leukocyte antigen (HLA) as the primary point of interest. Initial Japanese studies revealed strong relationships between the HLA-I antigens A33 and B44 and PHN in the local population. Research has highlighted significant associations between the HLA-A3303, HLA-B4403, and HLA-DRB11302 alleles and PHN [56, 57]. In Korea, different HLA alleles were identified in patients with PHN than in healthy individuals, with a notable increase in the frequency of HLA-B44 in patients with PHN when compared with that in patients with HZ [58]. Notably, the affinity of VZV peptides for these HLA variants differed, with HLA-A02 showing a much greater affinity for VZV peptides than HLA-B44 [59]. HLA gene variants seem to be intertwined with the pathogenesis of PHN, although most related research is region-centric.

Disturbances in energy metabolism can affect nerve cell functionality and repair capabilities, which can accelerate the emergence of neuropathic pain. A particular study revealed noticeable differences in the genotype distribution and allele frequencies of the rs3783641 single-nucleotide polymorphism (SNP) in the GCH1 gene among the groups [60]. Research has identified correlations between AMPK gene (PRKAA1) polymorphisms and PHN [61]. Inflammation, neural signaling, and neurodevelopment-related pathways are critical in neuropathic pain research. One study analyzed 24 candidate genetic polymorphisms from 12 genes and revealed that only the variation in the P2X purinoceptor 7 (P2RX7) gene was associated with increased PHN susceptibility [62]. Another study using a GWAS revealed a significant association between the rs4773840 SNP in the ABCC4 gene and PHN [63]. These findings underscore the immense potential of genotypes as biomarkers for predicting PHN.

PHN is a multifaceted disease influenced by various genes and environmental factors. Current genetic tests analyze only specific genes, and other influential factors may impede accurate predictions. Only a handful of gene variations associated with PHN are known at present, and the accuracy of predictions based on these sequences may be less than ideal. Therefore, while genetic testing offers substantial potential, additional research is needed to confirm its reliability and broader application.

Proteomics and Metabolomics

In the specific context of PHN research, proteomics and metabolomics offer complementary insights. A remarkable study revealed crucial insights. Elevated expression of the S100A9 protein in the dorsal root ganglia following VZV infection was observed, hinting at its potential role in triggering acute inflammatory responses [64]. Furthermore, in patients with HZ, there was a notable increase in the expression of proteins linked to cell structure and epithelial tissue damage, leading to an increase in inflammatory agents. Another study showed that the glucose-alanine cycle, tryptophan metabolism, tyrosine metabolism, lactose degradation, and malate–aspartate shuttle are the five major metabolic pathways involved in PHN evolution using pathway analysis [65]. The combined biomarker model accurately predicts PHN. In PHN sufferers, disturbances in fatty acid metabolites combined with heightened inflammatory triggers seemed to negatively impact serotonin metabolism, compromising inhibitory systems and amplifying neural sensitivity. The high accuracy of the metabolomics analysis indicates the potential for predicting HZ-induced PHN. It can also be used to understand the pathogenesis and metabolic pathways of diseases. This study has certain limitations. Metabolites are sensitive to many factors, and additional key metabolites may be found in multicenter, large-sample prospective studies.

Epidermal Nerve Fibers

Damage to nerve endings and nerve fibers caused by viral infection and inflammation, as well as abnormal repair, might be significant causes of acute HZ neuralgia and PHN. Therefore, epidermal nerve fiber testing may be a useful tool and potential biomarker in future research in patients with PHN.

Quantification of Small Nerve Fibers

An analysis comparing intraepidermal nerve fiber density (IENFD) between patients with PHN and PHN-free controls highlighted a significant association between a pronounced reduction in cutaneous sensory nerve endings and the occurrence of PHN following an HZ outbreak [66]. Furthermore, a controlled investigation discerned a correlation between intraepidermal nerve innervation density and the onset of PHN, noting a markedly increased nerve fiber density in patients without PHN [67]. When comparing affected and unaffected skin areas in patients with PHN, a stark reduction in IENFD was evident on the affected side [68]. Given the parallels in the transmission pathways of itch and pain, experts postulate an intrinsic connection between pruritus and pain etiologies [69]. Remarkably, as one patient’s pruritus symptoms receded, subsequent skin biopsies indicated a restoration of nerve fiber density to typical levels [70]. It is possible that PHN is a neurological anomaly tied to the depletion of nociceptors. Avoiding PHN might hinge on retaining a baseline density of primary nociceptor neurons. Consequently, epidermal innervation density could act as an indicator for predicting the likelihood of PHN pain.

Functionality of Small Nerve Fibers

Assessing IENFD in skin samples from patients with PHN, researchers identified an inverse relationship between atypical pain severity and the extent of decline in skin nerve innervation [68]. In contrast, direct assessments of C-fiber function indicate a direct link between pain and irregular pain severity [71]. This apparent disparity arises from the different metrics used to gauge peripheral nerve quantity versus function. Diminished C-fibers do not always equate to a reduction in IENFD. Pain accompanied by sensory dysfunction typically signifies a less favorable prognosis, whereas patients devoid of sensory anomalies often exhibit improved medication responsiveness [72]. Further subdivisions based on patients’ sensory profiles revealed marked variations in pain duration across groups [73]. In subjects who experienced PHN for less than 1 year, persistent pain intensity was directly correlated with dynamic mechanical stimulation-related abnormal pain intensity. This relationship was not found in patients with persistent PHN for more than a year [74]. Assessing small-fiber nerve function could pave the way for superior biological markers, differentiating PHN patient clusters and progression phases.

Notably, pathological vibration sensations in patients’ lower extremities predicted PHN with an impressive 70% sensitivity. However, the functions of nociceptive C fibers and parasympathetic fibers are consistent between patients with and without PHN [75]. These findings suggest that preexisting large-fiber conduction anomalies, particularly those linked with latent polyneuropathy, play a crucial role in PHN progression. Further studies have shown that individuals exhibiting both mechanical hypoesthesia and hyperalgesia/abnormal pain during acute herpetic zoster (AHZ) eventually develop PHN [76, 77]. Intriguingly, reduced thermal sensation during AHZ seems to serve as a protective mechanism against PHN [78]. Thermal hyperalgesia, a chief symptom of peripheral sensitization, along with distant body part hyposensitivity and hyperalgesia, might directly correlate with the neural pathways spanning the spinal cord. Inflammation within the central nervous system, coupled with the severity of nerve damage during AHZ, appears to profoundly influence the development of PHN. With advancements in medical sciences leading to noninvasive, efficient, and automated testing, these issues are expected to be reduced. Furthermore, quantitative analyses of small nerve fibers can provide accurate, quick, and user-friendly data for PHN prediction.

Magnetic Resonance Imaging

The transition from acute HZ to PHN is characterized by significant alterations in both the structure and function of the brain (Fig. 3). Research has shown that there is a loss of volume in gray matter (GM) regions accompanied by functional shifts in the insula, brainstem, and frontal lobe in both patients with HZ and PHN. Intriguingly, these patients can display varied brain changes in areas such as the cerebellar tonsil, central anterior gyrus, and temporal, occipital, and parietal lobes, potentially highlighting risk factors for PHN development [79]. Notably, in contrast to their HZ counterparts, patients with PHN have decreased GM volume in regions such as the left hippocampal gyrus, nucleus accumbens, and precentral gyrus but an increase in the right pulvinar [80]. In a side-by-side comparison of patients with PHN and HZ, irregularities in areas such as the left cerebellar tonsil, corpus callosum, and left lentiform nucleus emerged as potential precursors to the HZ–PHN transition [81]. Compared with patients with HZ, patients with PHN typically exhibit reduced thicknesses in the left insular and frontal opercular cortex (LFOP4) and the left motor cortex (L3B). These reductions in LFOP4 and L3B may be pivotal in signifying the transition from HZ to PHN, as the thickness of these areas is inversely related to the duration of both HZ and PHN [82].

Fig. 3
figure 3

The application of magnetic resonance in predicting postherpetic neuralgia. BGN basal ganglia network, DMN default mode network, DTI diffusion tensor imaging, ERN emotion regulation network, fMRI functional magnetic resonance imaging, GM gray matter, L3B left motor cortex, LFOP4 left insular and frontal opercular cortex, PAG periaqueductal gray matter, RVM rostral ventromedial medulla, SN salience network

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Huang’s group pioneered the creation of classification models with high sensitivity and specificity by investigating intrinsic brain activity and employing fMRI-based categorization in patients with HZ and PHN [83]. From a broader perspective, the progression from HZ to PHN triggered considerable fluctuations in localized brain activity in pain-associated regions, such as the frontal lobe, thalamus, cerebellum, brainstem, limbic system, and temporal lobes [84]. These functional modifications might facilitate the progression from HZ to PHN, potentially causing persistent chronic pain in patients with PHN. As HZ progresses to PHN, there is a significant surge in neural activity within broad regions of the cerebellum and a notable decrease in the occipital, temporal, parietal, and limbic lobes [85]. These changes, evaluated by fMRI, provide vital insights for predicting PHN onset.

An investigation of diffusion tensor imaging (DTI) data from patients with HZ and PHN revealed light anomalies in the diffusion patterns of white matter fibers in patients with PHN [86]. This diffusion irregularity suggests alterations in the microstructure of the white matter, potentially jeopardizing communication between relevant brain sections and influencing the broader neural re-encoding linked to PHN. In comparison, patients with PHN exhibited more pronounced microstructural distortions in zones associated with HZ-PHN evolution than did patients with HZ. An illustrative study encompassing five patients with HZ revealed an increase in functional connectivity between the left superior frontal gyrus (SFG) and right inferior frontal gyrus (IFG) in patients progressing to PHN [87]. Variations in brain region activation might be pivotal markers and underlying mechanisms for PHN onset.

Resting-state fMRI scans have identified inconsistencies in the neural connections between networks such as the default mode network (DMN), salience network (SN), emotion regulation network (ERN), and basal ganglia network (BGN) in patients with PHN and HZ relative to healthy controls. Notably, abnormalities in the DMN-BGN and internal BGN connections were also prevalent among patients with PHN [88]. While the pain intensity in patients with HZ correlated positively with network activity, patients with PHN did not show a marked increase in network connectivity [89]. This divergence necessitates further exploration into the kinds of abnormalities that could presage the onset of PHN. Given its indirect method of gauging neural activity through changes in brain oxygen levels, fMRI navigates complex physical and physiological terrains. This means that fMRI is not always unequivocal in interpreting brain activity, nor can it achieve precise single-neuron measurements. Additionally, the necessity for baseline imaging before capturing any response extends its duration. The steep financial requisites for fMRI equipment and expertise further limit its accessibility.

Other Biomarkers

Electromyography (EMG) serves as a diagnostic technique for gauging electrical activity within muscles, predominantly aiding in identifying muscle and nerve dysfunctions. A study examining EMG data in 91 patients revealed that compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes in the afflicted limb’s median nerve were autonomous factors influencing PHN [13]. These amplitudes demonstrated robust predictive ability for PHN. However, despite its diagnostic and therapeutic significance in neuropathic pain, EMG has inherent limitations. Specifically, while EMG easily examines and quantifies muscle and nerve electrical activity, it cannot directly measure pain intensity. Its application also mandates specialized equipment and trained practitioners, potentially constraining its accessibility due to varying costs and availability in certain areas.

Infrared thermography has potential for providing valuable data regarding the site and intensity of neuropathic pain. A study revealed that a heightened temperature disparity between the two sides significantly increased the incidence of PHN [90]. However, due to variations in inclusion benchmarks and participant numbers, some research contends that infrared thermography does not possess robust predictive power for PHN onset [91]. To efficiently utilize this technique, there is a need for technical support, dedicated equipment, and the knowledge of experienced medical professionals for accurate interpretation. Depending solely on this method might not capture the full spectrum of pain-related information, underlining the importance of combining this method with other medical documentation and physical assessments.

Conclusion and Future Perspectives

Biomarkers rooted in tangible clinical evaluations aligned with disease genesis provide a benchmark for disease risk assessment (Fig. 4). Alterations in blood components, such as cytokines and specific immune cells, indicate inflammation levels and the state of immunosuppression during acute phases, with proven predictive power for PHN. Molecular shifts linked to nerve damage indicate the scale of injury and can anticipate subsequent complications. Variability in gene expression can segregate high-risk and low-risk factions. Advances in proteomics and metabolomics can help researchers delve into protein interactions or detect irregularities in bodily metabolites, opening doors to tailored risk predictions and potentially revealing more potent biomarkers. Diagnostic methods such as neuropathy detection and EMG provide personalized insights, providing a roadmap for preventing PHN and initiating early treatments (Table 1). However, as enlightening as biomarker studies are, constraints such as exorbitant costs, limited study samples, and unrepresentative cohorts might hinder their reach.

Fig. 4
figure 4

Potential biomarkers for postherpetic neuralgia: a laboratory test overview. IL interleukin, NK natural killer, NLR neutrophil-to-lymphocyte ratio, PHN postherpetic neuralgia, VZV varicella-zoster virus

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Table 1 Potential biomarkers for postherpetic neuralgia: an examination overview
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The combination of both risk factors and biomarkers represents a holistic and precise health and disease risk assessment approach. Biomarkers, as early warning systems, can flag potential disease markers. By examining these markers in biological samples, disease presence or predisposition becomes discernible, facilitating presymptomatic predictions. This knowledge, when combined with risk factor data, refines an individual’s disease risk evaluation. Tailoring treatment blueprints and preventive steps to resonate with a person’s risk factors and biomarkers not only heightens treatment success but also mitigates unwanted repercussions. Similar to intricate neurological ailments such as Alzheimer’s disease, a solitary biomarker is unlikely to be a definitive predictor for PHN. However, when modern analytical tools, such as neural networks, artificial intelligence, or machine learning algorithms, are used to create a composite PHN biomarker profile, there is a strong chance of revealing the mysteries of PHN and developing innovative treatments.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. This review advances the understanding of postherpetic neuralgia (PHN) by summarizing current research on biological markers, thereby laying the groundwork for future studies in an under-researched field. It underscores the necessity of multicenter pilot studies to identify specific, sensitive biomarkers that could improve disease diagnosis and management. Despite the potential selection bias due to search methodologies on PubMed that may overlook less common techniques or specifically focused studies, it elucidates the clinical significance of such markers in early disease detection. However, accessibility and affordability of appropriate diagnostic tests pose a challenge, given the current lack of highly sensitive markers and the prohibitive cost of more comprehensive methods like functional MRI.

Research to date is mainly single-center and may not be representative, suffering from methodological limitations such as inclusivity of only late-stage patients and a paucity of baseline data. Additionally, patient heterogeneity across studies reflects a lack of generalizable findings. Despite these challenges, some correlations have emerged, guiding the choice of detection methods and informing protocol designs for future research. From a cost-effectiveness perspective, the review suggests tiered screening strategies, prioritizing simple, cost-effective tests for broader populations and reserving more expensive, invasive procedures for those at greatest risk. Such an approach not only prevents unnecessary diagnostic resource expenditure but also mitigates the possibility of post-disease complications, thereby reducing overall social and medical care costs.

Promptly administering antiviral therapy and ensuring its full course can markedly reduce the risk of PHN, with those at increased risk receiving the greatest benefit [92, 93]. Implementing immediate pain management, in tandem with mood stabilization and sleep induction, has led to a significant decline in patients with PHN, especially in high-risk populations. In addition to drug-based interventions, more invasive treatments, such as local tissue procedures, nerve root interventions, and pulsed radio frequency, are recommended for those at elevated risk, as they can reduce complication rates [94, 95]. Traditional Chinese medicine such as acupuncture has shown potential for treating pain in certain areas, although additional extensive studies are needed [96]. In the aftermath of PHN, it is vital to deploy robust measures to counter sleep disturbances and emotional irregularities stemming from persistent pain, as these can exacerbate pain duration [97, 98]. Biological markers play a pivotal role in gauging the success of treatments and how individuals respond. Periodic assessment of these markers can track the trajectory and impact of treatments, allowing for timely alterations to therapeutic regimens.

Current research endeavors focused on PHN predominantly involve the collection of patient blood, tumor samples, and microbiome data. Research has focused on assimilating genomic information (mutations or methylation) and immune functionalities (T-cell activity) from easily obtainable sources such as blood, fecal matter, and urine to explore elements that drive the onset and progression of PHN. Considering the pressing medical demand for more forward-looking PHN investigations, collating and dissecting biomarker data could offer a valuable foundation for clinical application.